One of the long-awaited promises of the human genome sequencing project is the identification of genes involved in common human disease. Human geneticists have identified genes involved in type 2 diabetes, asthma, and many other common diseases. Despite these successes, there has been little translational impact of identifying these common disease genes because the relative risk of developing disease for carriers of each defective gene is small. Although this fact is not surprising to geneticists, it bgs the question of what type of information could be added to genetic risk data to increase the predictive power of who is at highest or lowest risk for any particular disease. In this vein, ther is great interest in the potential for epigenetic markers to add predictive value to genetic risk data. There is perhaps no better case for a major role for epigenetic effects in common disease than colon cancer. Colon cancer accounts for more than 10% of all invasive cancer cases in the United States and more than 100,000 new cases are diagnosed each year. It is the third most common cancer in both men and women and the third leading cause of cancer deaths. Epigenetic alterations are associated with both increased risk of disease and tumor progression. Moreover, there is compelling evidence linking environmental influences such as western diets and cigarette smoking with increased risk of colon cancer. Our hypothesis is that systemic epigenetic differences and environmentally-induced epigenetic changes are associated with increased risk of colon cancer and that these differences can be distinguished in colon mucosa that appears otherwise normal. We published the results of a pilot experiment that compared the normal colon mucosa of cancer patients with the normal colon mucosa of individuals who did not have cancer or colon polyps and found highly significant differences in DNA methylation at many of the genes involved in the metabolism of lipids and carbohydrates (dietary components that may be involved in increased risk of colon cancer), as well as insulin signaling. In this project, we propose to validate a set of these DNA methylation differences that are likely to result from dietary factors in cancer-prone individuals. If validated in an independent group of patients, this set of DNA methylation differences will constitute an epigenetic metabolic signature of colon cancer risk. A collection of such biomarkers would constitute a quantitative, clinically useful biochemical tool to assess cancer risk.